An acetylcysteine injection and its preparation method

Abstract

The present invention discloses an acetylcysteine injection and a preparation method thereof, belonging to the technical field of pharmaceutical injection preparation. The injection comprises the following components in percentage by weight: 1%-4% of acetylcysteine, 2%-8% of a stabilizer, and 0.01%-0.05% of an antioxidant, with the balance being water; wherein, the stabilizer comprises zinc sulfate and polyporus umbellatus polysaccharide. The acetylcysteine injection has the advantages of strong stability, long storage time, difficult decomposition and deterioration of active ingredients, and low impurity content, and can effectively solve the problem of easy degradation existing in the acetylcysteine injection in the prior art.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical injections, and particularly relates to an acetylcysteine injection and a preparation method thereof. Background Art

[0002] Acetylcysteine is a precursor of reduced glutathione, which can scavenge oxygen free radicals in the body and protect liver cells. Acetylcysteine injection is a liver-protecting drug, mainly used for the early treatment of liver failure, which can reduce bilirubin and increase the activity of prothrombin.

[0003] The existing preparation process of acetylcysteine injection includes preparing a NaOH solution with a certain concentration to dissolve acetylcysteine and disodium edetate, then making up the volume, adjusting the pH, filtering and sterilizing, and finally filling to obtain the acetylcysteine injection. The complex preparation steps of the existing acetylcysteine injection will cause the degradation of acetylcysteine raw materials during the preparation process, resulting in high impurity content and various types in the prepared acetylcysteine injection, and obvious impurity growth during storage. Therefore, it is of great significance to develop an acetylcysteine injection with low impurity content and high storage stability for improving the medication safety of patients. Summary of the Invention

[0004] Aiming at the above deficiencies in the prior art, the present invention provides an acetylcysteine injection and a preparation method thereof. The acetylcysteine injection has the advantages of strong stability, long storage time, difficult decomposition and deterioration of active ingredients, and low impurity content, and can effectively solve the problem of easy degradation existing in the existing acetylcysteine injection.

[0005] To achieve the above object, the technical solution adopted by the present invention to solve its technical problems is:

[0006] An acetylcysteine injection, comprising the following components in percentage by weight: 1%-4% of acetylcysteine, 2%-8% of stabilizer, and 0.01%-0.05% of antioxidant, and the rest is water.

[0007] Further, it comprises the following components in percentage by weight: 3%-4% of acetylcysteine, 5%-8% of stabilizer, 0.02%-0.03% of antioxidant, and the rest is injection water.

[0008] Further, the stabilizer includes zinc sulfate and polyporus umbellatus polysaccharide.

[0009] Further, the mass ratio of zinc sulfate is 3%-4%, and the mass ratio of polyporus umbellatus polysaccharide is 2%-4%.

[0010] Further, the antioxidant is disodium edetate.

[0011] The preparation method of the above-mentioned acetylcysteine injection comprises the following steps:

[0012] (1) At 40 - 50 °C under a nitrogen environment, zinc sulfate and acetylcysteine are successively added to anaerobic injection water, stirred until dissolved, and the pH of the solution is adjusted to 6 - 8 to obtain an acetylcysteine solution;

[0013] (2) Under a nitrogen environment, disodium edetate is added to anaerobic injection water and stirred until dissolved to obtain a disodium edetate solution;

[0014] (3) Under a nitrogen environment, polyporus polysaccharide is added to anaerobic injection water and stirred until dissolved to obtain a polyporus polysaccharide solution;

[0015] (4) Under a nitrogen environment, the disodium edetate solution and the polyporus polysaccharide solution are successively and slowly added dropwise to the acetylcysteine solution, stirred and mixed evenly, made up to volume, and then filtered, encapsulated, and sterilized by high-pressure steam to obtain the product.

[0016] Further, after the zinc sulfate is dissolved in step (1), acetylcysteine is added thereto.

[0017] Further, the pore size of the filter device in step (4) is 0.22 microns.

[0018] Further, in step (4), the high-pressure steam sterilization temperature is 113 - 123 °C, and the sterilization time is 10 - 15 min.

[0019] The beneficial effects produced by the present invention are as follows:

[0020] In the present invention, under a nitrogen environment, anaerobic injection water is used as a solvent, which can reduce the contact between acetylcysteine and oxygen from the source, reduce the risk of oxidation during the preparation process, and improve the effectiveness of the drug.

[0021] In the present invention, a stabilizer is added to improve the stability of acetylcysteine and prevent it from being oxidized and decomposed during storage. Specifically, during the preparation process, zinc sulfate is first dissolved to prepare a zinc sulfate solution, and then acetylcysteine is added thereto. During the dissolution process of acetylcysteine, the sulfhydryl group inside it forms a complex with the zinc ions in the solution, which can improve the stability of the sulfhydryl group, and further improve the stability of acetylcysteine and reduce the risk of oxidation; then a disodium edetate solution and a polyporus polysaccharide solution are prepared. Disodium edetate has strong antioxidant properties and can preferentially combine with metal ions and oxygen to assist in improving the stability of acetylcysteine; and polyporus polysaccharide is a macromolecular polysaccharide component. During the stirring process of the solution, the macromolecular polysaccharide can act as a protective layer to wrap acetylcysteine inside the macromolecular polysaccharide, further improving the stability of acetylcysteine, preventing it from being oxidized during storage, and thus improving the stability of acetylcysteine and reducing the content of impurities in the injection.

[0022] The preparation method in the present invention is operated in a nitrogen environment throughout the process, reducing the participation of oxygen from the source, improving the stability of the injection solution, and the preparation method in this application is simple, easy to operate, and can be applied in batches. Detailed implementation manners

[0023] In order to make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the following further details the present invention in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention, that is, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments.

[0024] Therefore, the following detailed description of the provided embodiments of the present invention is not intended to limit the scope of the claimed present invention, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative efforts fall within the scope of protection of the present invention.

[0025] It should be noted that relational terms such as "first" and "second" are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprising", "including" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements not only includes those elements, but also includes other elements not expressly listed, or also includes elements inherent to such process, method, article or device. Without further limitation, an element defined by the statement "including one..." does not exclude the existence of additional identical elements in the process, method, article or device including the element.

[0026] The features and performance of the present invention will be further described in detail below in conjunction with embodiments.

[0027] Example 1

[0028] An acetylcysteine injection solution, comprising the following components in weight percentages: 3% of acetylcysteine, 2% of zinc sulfate, 2% of polyporus umbellatus polysaccharide, and 0.01% of disodium edetate, with the rest being water.

[0029] The preparation method of the above-mentioned acetylcysteine injection solution includes the following steps:

[0030] (1) At 40°C and in a nitrogen environment, add zinc sulfate to anaerobic injection water, stir until dissolved, then add acetylcysteine thereto, stir until dissolved, and adjust the pH of the solution to 7 with sodium hydroxide solution to obtain an acetylcysteine solution;

[0031] (2) Under a nitrogen atmosphere, add disodium edetate to anaerobic water for injection and stir until dissolved to obtain a disodium edetate solution.

[0032] (3) Under a nitrogen atmosphere, add polysaccharide from polyporus umbellatus to anaerobic water for injection and stir until dissolved to obtain a polysaccharide from polyporus umbellatus solution.

[0033] (4) Under a nitrogen atmosphere, slowly add the disodium edetate solution and the polysaccharide from polyporus umbellatus solution to the acetylcysteine solution in sequence, stir and mix evenly, adjust the pH of the solution to 7 using hydrochloric acid or sodium hydroxide, make up the volume, then filter through an aluminum membrane with a pore size of 0.22 microns, package, and perform high-pressure steam sterilization at 113 °C for 15 minutes to obtain the product.

[0034] Example 2

[0035] An acetylcysteine injection, comprising the following components by weight percentage: acetylcysteine 3%, zinc sulfate 4%, polysaccharide from polyporus umbellatus 4%, and disodium edetate 0.05%, with the balance being water.

[0036] The preparation method of the above-mentioned acetylcysteine injection comprises the following steps:

[0037] (1) At 50 °C and under a nitrogen atmosphere, add zinc sulfate to anaerobic water for injection and stir until dissolved, then add acetylcysteine thereto and stir until dissolved, and adjust the pH of the solution to 8 using a sodium hydroxide solution to obtain an acetylcysteine solution.

[0038] (2) Under a nitrogen atmosphere, add disodium edetate to anaerobic water for injection and stir until dissolved to obtain a disodium edetate solution.

[0039] (3) Under a nitrogen atmosphere, add polysaccharide from polyporus umbellatus to anaerobic water for injection and stir until dissolved to obtain a polysaccharide from polyporus umbellatus solution.

[0040] (4) Under a nitrogen atmosphere, slowly add the disodium edetate solution and the polysaccharide from polyporus umbellatus solution to the acetylcysteine solution in sequence, stir and mix evenly, adjust the pH of the solution to 7 using hydrochloric acid or sodium hydroxide, make up the volume, then filter through an aluminum membrane with a pore size of 0.22 microns, package, and perform high-pressure steam sterilization at 123 °C for 10 minutes to obtain the product.

[0041] Example 3

[0042] An acetylcysteine injection, comprising the following components by weight percentage: acetylcysteine 4%, zinc sulfate 3%, polysaccharide from polyporus umbellatus 2%, and disodium edetate 0.02%, with the balance being water.

[0043] The preparation method of the above-mentioned acetylcysteine injection comprises the following steps:

[0044] (1) At 50 °C under a nitrogen environment, zinc sulfate is added to anaerobic injection water and stirred until dissolved. Then, acetylcysteine is added thereto and stirred until dissolved. The pH of the solution is adjusted to 6 using a sodium hydroxide solution to obtain an acetylcysteine solution;

[0045] (2) Under a nitrogen environment, disodium edetate is added to anaerobic injection water and stirred until dissolved to obtain a disodium edetate solution;

[0046] (3) Under a nitrogen environment, polyporus umbellatus polysaccharide is added to anaerobic injection water and stirred until dissolved to obtain a polyporus umbellatus polysaccharide solution;

[0047] (4) Under a nitrogen environment, the disodium edetate solution and the polyporus umbellatus polysaccharide solution are sequentially and slowly added dropwise to the acetylcysteine solution, stirred and mixed evenly. The pH of the solution is adjusted to 7 using hydrochloric acid or sodium hydroxide, made up to volume, and then filtered through an aluminum film with a pore size of 0.22 microns, encapsulated, and subjected to high-pressure steam sterilization at 117 °C for 15 minutes to obtain the product.

[0048] Example 4

[0049] An acetylcysteine injection, comprising the following components in weight percentages: acetylcysteine 4%, zinc sulfate 4%, polyporus umbellatus polysaccharide 3%, and disodium edetate 0.03%, with the balance being water.

[0050] The preparation method of the above-mentioned acetylcysteine injection comprises the following steps:

[0051] (1) At 45 °C under a nitrogen environment, zinc sulfate is added to anaerobic injection water and stirred until dissolved. Then, acetylcysteine is added thereto and stirred until dissolved. The pH of the solution is adjusted to 7 using a sodium hydroxide solution to obtain an acetylcysteine solution;

[0052] (2) Under a nitrogen environment, disodium edetate is added to anaerobic injection water and stirred until dissolved to obtain a disodium edetate solution;

[0053] (3) Under a nitrogen environment, polyporus umbellatus polysaccharide is added to anaerobic injection water and stirred until dissolved to obtain a polyporus umbellatus polysaccharide solution;

[0054] (4) Under a nitrogen environment, the disodium edetate solution and the polyporus umbellatus polysaccharide solution are sequentially and slowly added dropwise to the acetylcysteine solution, stirred and mixed evenly. The pH of the solution is adjusted to 7 using hydrochloric acid or sodium hydroxide, made up to volume, and then filtered through an aluminum film with a pore size of 0.22 microns, encapsulated, and subjected to high-pressure steam sterilization at 120 °C for 15 minutes to obtain the product.

[0055] Comparative Example 1

[0056] An acetylcysteine injection, comprising components in the following weight percentages: 4% of acetylcysteine, 3% of polyporus umbellatus polysaccharide, and 0.03% of disodium edetate, with the balance being water.

[0057] The preparation method of the above-mentioned acetylcysteine injection comprises the following steps:

[0058] (1) At 45°C and in a nitrogen environment, add acetylcysteine to anaerobic injection water, stir until dissolved, and adjust the pH of the solution to 7 with sodium hydroxide solution to obtain an acetylcysteine solution.

[0059] (2) In a nitrogen environment, add disodium edetate to anaerobic injection water, stir until dissolved, to obtain a disodium edetate solution.

[0060] (3) In a nitrogen environment, add polyporus umbellatus polysaccharide to anaerobic injection water, stir until dissolved, to obtain a polyporus umbellatus polysaccharide solution.

[0061] (4) In a nitrogen environment, slowly dropwise add the disodium edetate solution and the polyporus umbellatus polysaccharide solution to the acetylcysteine solution in sequence, stir and mix evenly, adjust the pH of the solution to 7 with hydrochloric acid or sodium hydroxide, make up the volume, then filter with an aluminum film with a pore size of 0.22 microns, package, and perform high-pressure steam sterilization at 120°C for 15 minutes to obtain the product.

[0062] Comparative Example 2

[0063] An acetylcysteine injection, comprising components in the following weight percentages: 4% of acetylcysteine, 4% of zinc sulfate, and 0.03% of disodium edetate, with the balance being water.

[0064] The preparation method of the above-mentioned acetylcysteine injection comprises the following steps:

[0065] (1) At 45°C and in a nitrogen environment, add zinc sulfate to anaerobic injection water, stir until dissolved, then add acetylcysteine thereto, stir until dissolved, and adjust the pH of the solution to 7 with sodium hydroxide solution to obtain an acetylcysteine solution.

[0066] (2) In a nitrogen environment, add disodium edetate to anaerobic injection water, stir until dissolved, to obtain a disodium edetate solution.

[0067] (4) In a nitrogen environment, slowly dropwise add the disodium edetate solution to the acetylcysteine solution, stir and mix evenly, adjust the pH of the solution to 7 with hydrochloric acid or sodium hydroxide, make up the volume, then filter with an aluminum film with a pore size of 0.22 microns, package, and perform high-pressure steam sterilization at 120°C for 15 minutes to obtain the product.

[0068] Comparative Example 3

[0069] An acetylcysteine injection, comprising the following components in weight percentages: 4% of acetylcysteine, 4% of zinc sulfate, 3% of tremella polysaccharide, and 0.03% of disodium edetate, with the balance being water.

[0070] The preparation method of the above-mentioned acetylcysteine injection comprises the following steps:

[0071] (1) At 45°C under a nitrogen environment, zinc sulfate is added to anaerobic injection water, stirred until dissolved, then acetylcysteine is added thereto and stirred until dissolved, and the pH of the solution is adjusted to 7 with a sodium hydroxide solution to obtain an acetylcysteine solution;

[0072] (2) Under a nitrogen environment, disodium edetate is added to anaerobic injection water and stirred until dissolved to obtain a disodium edetate solution;

[0073] (3) Under a nitrogen environment, tremella polysaccharide is added to anaerobic injection water and stirred until dissolved to obtain a tremella polysaccharide solution;

[0074] (4) Under a nitrogen environment, the disodium edetate solution and the tremella polysaccharide solution are sequentially and slowly added dropwise to the acetylcysteine solution, stirred and mixed evenly, the pH of the solution is adjusted to 7 with hydrochloric acid or sodium hydroxide, made up to volume, then filtered through an aluminum film with a pore size of 0.22 microns, encapsulated, and subjected to high-pressure steam sterilization at 120°C for 15 minutes to obtain.

[0075] Test Example

[0076] The quality and stability of different injections were detected by the high-performance liquid chromatography method recorded in the Chinese Pharmacopoeia 2020 Edition. Among them, during the stability detection, the light treatment condition was 4500 Lx, and the high-temperature treatment condition was 60°C.

[0077] Related substances detection:

[0078] Chromatographic column: C18 column;

[0079] Mobile phase: 0.01 mol / L phosphate buffer - methanol (95:5);

[0080] Detection wavelength: 210 nm;

[0081] Injection volume: 20 μL;

[0082] Flow rate: 1.5 ml / min;

[0083] Column temperature: 20°C;

[0084] Among them, the peak emergence time of cysteine is 5 - 6 min, the peak emergence time of N-N'-diacetylcysteine is 10 - 11 min, and the peak emergence time of N-S-diacetylcysteine is 13 - 15 min.

[0085] Perform quality inspection on the acetylcysteine injection solutions prepared in Examples 1 - 4 and Comparative Examples 1 - 3. The specific inspection results are shown in Tables 1 - 2; after the stability tests of the injection solutions in Examples 1 - 4 and Comparative Examples 1 - 3 are completed, continue to perform quality inspection on them, and the specific results are shown in Table 3.

[0086]

[0087]

[0088] Table 1: Stability test results

[0089] It can be seen from the results in Table 1 that after the injection solutions in Examples 1 - 4 and Comparative Examples 1 - 3 are treated by light and high temperature, the apparent quality of the injection solutions has not changed. The pH value of the injection solutions in Examples 1 - 4 has no obvious change compared with that before treatment, and the pH value of the injection solutions in Comparative Examples 1 - 3 has decreased slightly compared with that before treatment.

[0090] Table 2: Quality inspection results

[0091]

[0092] It can be seen from Table 2 that the content of the active ingredient in the acetylcysteine injection solutions prepared in Examples 1 - 4 is relatively high, and the content of related substances is relatively low. While in Comparative Examples 1 - 3, the content of the active ingredient has decreased and the content of related substances has increased. It is speculated that after adjusting the preparation method, during the preparation or disinfection process, the active ingredient is oxidized and degraded, resulting in a decrease in the content of the active ingredient.

[0093] Table 3: Quality inspection results of the injection solution after light exposure

[0094]

[0095] Table 4: Quality inspection results of the injection solution after high temperature treatment

[0096]

[0097]

[0098] It can be seen from the results in Tables 3 - 4 that after the stability test, the content of the active ingredient in the injection solutions of Examples 1 - 4 is still relatively high, while the content of the active ingredient in the injection solutions of Comparative Examples 1 - 3 has decreased and the content of other substances has increased. It is speculated that after adjusting the preparation method, the stability of acetylcysteine in the injection solution is insufficient and it is degraded under the action of high temperature or light.

[0099] In summary, the preparation method in the present application can effectively improve the stability of acetylcysteine injection, reduce the degradation during storage, and thus extend the storage time of the injection.

Claims

1. An acetylcysteine ​​injection, characterized in that: The invention comprises the following components in weight percentage: 1%-4% acetylcysteine, 0.01-0.05% stabilizer and antioxidant, and the rest is water; The stabilizer is zinc sulfate and Polyporus polysaccharide, the mass proportion of the zinc sulfate is 3%-4%, the mass proportion of the Polyporus polysaccharide is 2%-4%, and the antioxidant is disodium edetate.

2. The acetylcysteine ​​injection according to claim 1, characterized in that The invention comprises the following components in percentage by weight: 3%-4% of acetylcysteine, 5%-8% of a stabilizer, 0.02%-0.03% of an antioxidant, and the rest being water for injection.

3. The method for preparing acetylcysteine ​​injection according to claim 1 or 2, characterized in that, The following steps are involved: (1) At 40-50°C and in a nitrogen environment, zinc sulfate and acetylcysteine ​​are added to oxygen-free water for injection in sequence, stirred until dissolved, and the pH of the solution is adjusted to 6-8 to prepare an acetylcysteine ​​solution; (2) Add edetate disodium to oxygen-free water for injection under nitrogen atmosphere and stir until dissolved to prepare edetate disodium solution; (3) Under nitrogen environment, add Polyporus polysaccharide to oxygen-free water for injection and stir until dissolved to prepare Polyporus polysaccharide solution; (4) Under a nitrogen environment, the edetate disodium solution and the polyporus polysaccharide solution are slowly added dropwise to the acetylcysteine ​​solution in sequence, stirred to mix, fixed to volume, and then filtered, packaged, and sterilized by high-pressure steam to obtain the product.

4. The method for preparing acetylcysteine ​​injection as claimed in claim 3, characterized in that: After the zinc sulfate is dissolved in step (1), acetylcysteine ​​is added thereto.

5. The method for preparing acetylcysteine ​​injection as claimed in claim 3, characterized in that, The pore size of the filter device in step (4) is 0.22 microns.

6. The method for preparing acetylcysteine ​​injection according to claim 3, characterized in that: The high-pressure steam sterilization temperature is 113-123℃, and the sterilization time is 10-15min.

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